Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

BMC Med Genet. 2020 Mar 12;21(1):50. doi: 10.1186/s12881-020-0986-5.


Background: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation.

Methods: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced.

Results: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%).

Conclusion: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

Keywords: Congenital heart defects; Mutational analysis; Noonan syndrome; PTPN11; RASopathy; SHP-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Mutational Analysis
  • Family
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Heart Defects, Congenital / epidemiology
  • Heart Defects, Congenital / genetics
  • Humans
  • India / epidemiology
  • Infant
  • Infant, Newborn
  • Male
  • Noonan Syndrome / epidemiology
  • Noonan Syndrome / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Young Adult


  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11